scholarly journals Lack of Cas13a inhibition by anti-CRISPR proteins from Leptotrichia prophages

2021 ◽  
Author(s):  
Alexander J Meeske ◽  
Matthew C Johnson ◽  
Logan T Hille ◽  
Benjamin P Kleinstiver ◽  
Joseph Bondy-Denomy
Keyword(s):  
Nucleic Acid ◽  
Rna Cleavage ◽  
Nucleic Acid Binding ◽  
Bacterial Strains ◽  
Bioinformatics Analyses ◽  
Immune Systems ◽  
Adaptive Immune ◽  
Bona Fide ◽  
Adaptive Immune Systems

CRISPR systems are prokaryotic adaptive immune systems that use RNA-guided Cas nucleases to recognize and destroy foreign genetic elements, like bacteriophages and plasmids. To overcome CRISPR immunity, phages have evolved diverse families of anti-CRISPR proteins (Acrs), each of which inhibits the nucleic acid binding or cleavage activities of specific Cas protein families. Recently, Lin et al. (2020) described the discovery and characterization of 7 different Acr families (AcrVIA1-7) that inhibit type VI-A CRISPR systems, which use the nuclease Cas13a to perform RNA-guided RNA cleavage. In this Matters Arising article, we detail several inconsistencies that question the results reported in the Lin et al. (2020) study. These include inaccurate bioinformatics analyses, as well as reported experiments involving bacterial strains that are impossible to construct. The authors were unable to provide their published strains with which we might reproduce their experiments. We independently tested the Acr sequences described in Lin et al. (2020) in two different Cas13 inhibition assays, but could not detect anti-CRISPR activity. Taken together, our data and analyses prompt us to question the claim that AcrVIA1-7 reported in Lin et al. are bona fide type VI anti-CRISPR proteins.

scholarly journals Structures and Strategies of Anti-CRISPR-Mediated Immune Suppression

2020 ◽  
Vol 74 (1) ◽  
pp. 21-37 ◽  
Author(s):  
Tanner Wiegand ◽  
Shweta Karambelkar ◽  
Joseph Bondy-Denomy ◽  
Blake Wiedenheft
Keyword(s):  
Nucleic Acid ◽  
Protein Binding ◽  
Adaptive Immunity ◽  
Immune Suppression ◽  
Immune Systems ◽  
Adaptive Immune ◽  
Ribonucleoprotein Complexes ◽  
Binding Partners ◽  
Trade Offs ◽  
Adaptive Immune Systems

More than 50 protein families have been identified that inhibit CRISPR (clustered regularly interspaced short palindromic repeats)-Cas-mediated adaptive immune systems. Here, we analyze the available anti-CRISPR (Acr) structures and describe common themes and unique mechanisms of stoichiometric and enzymatic suppressors of CRISPR-Cas. Stoichiometric inhibitors often function as molecular decoys of protein-binding partners or nucleic acid targets, while enzymatic suppressors covalently modify Cas ribonucleoprotein complexes or degrade immune signaling molecules. We review mechanistic insights that have been revealed by structures of Acrs, discuss some of the trade-offs associated with each of these strategies, and highlight how Acrs are regulated and deployed in the race to overcome adaptive immunity.

scholarly journals An Evolutionary Link between Natural Transformation and CRISPR Adaptive Immunity

mBio ◽  
2012 ◽  
Vol 3 (5) ◽  
Author(s):  
Peter Jorth ◽  
Marvin Whiteley
Keyword(s):  
Gene Transfer ◽  
Horizontal Gene Transfer ◽  
Bacterial Diversity ◽  
Natural Transformation ◽  
Bacterial Species ◽  
Comparative Genomic ◽  
Content Type ◽  
Immune Systems ◽  
Adaptive Immune ◽  
Adaptive Immune Systems

ABSTRACTNatural transformation by competent bacteria is a primary means of horizontal gene transfer; however, evidence that competence drives bacterial diversity and evolution has remained elusive. To test this theory, we used a retrospective comparative genomic approach to analyze the evolutionary history ofAggregatibacter actinomycetemcomitans, a bacterial species with both competent and noncompetent sister strains. Through comparative genomic analyses, we reveal that competence is evolutionarily linked to genomic diversity and speciation. Competence loss occurs frequently during evolution and is followed by the loss of clustered regularly interspaced short palindromic repeats (CRISPRs), bacterial adaptive immune systems that protect against parasitic DNA. Relative to noncompetent strains, competent bacteria have larger genomes containing multiple rearrangements. In contrast, noncompetent bacterial genomes are extremely stable but paradoxically susceptible to infective DNA elements, which contribute to noncompetent strain genetic diversity. Moreover, incomplete noncompetent strain CRISPR immune systems are enriched for self-targeting elements, which suggests that the CRISPRs have been co-opted for bacterial gene regulation, similar to eukaryotic microRNAs derived from the antiviral RNA interference pathway.IMPORTANCEThe human microbiome is rich with thousands of diverse bacterial species. One mechanism driving this diversity is horizontal gene transfer by natural transformation, whereby naturally competent bacteria take up environmental DNA and incorporate new genes into their genomes. Competence is theorized to accelerate evolution; however, attempts to test this theory have proved difficult. Through genetic analyses of the human periodontal pathogenAggregatibacter actinomycetemcomitans, we have discovered an evolutionary connection between competence systems promoting gene acquisition and CRISPRs (clustered regularly interspaced short palindromic repeats), adaptive immune systems that protect bacteria against genetic parasites. We show that competentA. actinomycetemcomitansstrains have numerous redundant CRISPR immune systems, while noncompetent bacteria have lost their CRISPR immune systems because of inactivating mutations. Together, the evolutionary data linking the evolution of competence and CRISPRs reveals unique mechanisms promoting genetic heterogeneity and the rise of new bacterial species, providing insight into complex mechanisms underlying bacterial diversity in the human body.

scholarly journals Emerging evidence of an effect of salt on innate and adaptive immunity

2018 ◽  
Vol 34 (12) ◽  
pp. 2007-2014 ◽  
Author(s):  
Rhys D R Evans ◽  
Marilina Antonelou ◽  
Scott Henderson ◽  
Stephen B Walsh ◽  
Alan D Salama
Keyword(s):  
Laboratory Animal ◽  
Salt Intake ◽  
Natural Diet ◽  
Innate And Adaptive Immunity ◽  
Immune Systems ◽  
Adaptive Immune ◽  
Multiple Components ◽  
Excess Salt Intake ◽  
Adaptive Immune Systems ◽  
Recent Laboratory

AbstractSalt intake as part of a western diet currently exceeds recommended limits, and the small amount found in the natural diet enjoyed by our Paleolithic ancestors. Excess salt is associated with the development of hypertension and cardiovascular disease, but other adverse effects of excess salt intake are beginning to be recognized, including the development of autoimmune and inflammatory disease. Over the last decade there has been an increasing body of evidence demonstrating that salt affects multiple components of both the innate and adaptive immune systems. In this review we outline the recent laboratory, animal and human data, highlighting the effect of salt on immunity, with a particular focus on the relevance to inflammatory kidney disease.

scholarly journals CRISPR-Cas immunity repressed by a biofilm-activating pathway inPseudomonas aeruginosa

2019 ◽  
Author(s):  
Adair L. Borges ◽  
Bardo Castro ◽  
Sutharsan Govindarajan ◽  
Tina Solvik ◽  
Veronica Escalante ◽  
...  
Keyword(s):  
Genetic Screen ◽  
Type I ◽  
Two Component System ◽  
Component System ◽  
Forward Genetic Screen ◽  
Immune Systems ◽  
Adaptive Immune ◽  
Biofilm Production ◽  
Two Component ◽  
Adaptive Immune Systems

CRISPR-Cas systems are adaptive immune systems that protect bacteria from bacteriophage (phage) infection. To provide immunity, RNA-guided protein surveillance complexes recognize foreign nucleic acids, triggering their destruction by Cas nucleases. While the essential requirements for immune activity are well understood, the physiological cues that regulate CRISPR-Cas expression are not. Here, a forward genetic screen identifies a two-component system (KinB/AlgB), previously characterized in regulatingPseudomonas aeruginosavirulence and biofilm establishment, as a regulator of the biogenesis and activity of the Type I-F CRISPR-Cas system. Downstream of the KinB/AlgB system, activators of biofilm production AlgU (a σEorthologue) and AlgR, act as repressors of CRISPR-Cas activity during planktonic and surface-associated growth. AmrZ, another biofilm activator, functions as a surface-specific repressor of CRISPR-Cas immunity.Pseudomonasphages and plasmids have taken advantage of this regulatory scheme, and carry hijacked homologs of AmrZ, which are functional CRISPR-Cas repressors. This suggests that while CRISPR-Cas regulation may be important to limit self-toxicity, endogenous repressive pathways represent a vulnerability for parasite manipulation.

scholarly journals Epidemiological and evolutionary consequences of CRISPR-Cas reactivity

2021 ◽  
Author(s):  
Hélène Chabas ◽  
Viktor Müller ◽  
Sebastian Bonhoeffer ◽  
Roland R. Regoes
Keyword(s):  
Critical Threshold ◽  
Immune Systems ◽  
Adaptive Immune ◽  
Phage Evolution ◽  
Evolutionary Consequences ◽  
Adaptive Immune Systems ◽  
Control Challenge

AbstractAdaptive immune systems face a control challenge: they should react with enough strength to clear an infection while avoiding to harm their organism. CRISPR-Cas systems are adaptive immune systems of prokaryotes that defend against fast evolving viruses. Here, we explore the CRISPR-Cas control challenge and look how its reactivity, i.e. its probability to acquire a new resistance, impacts the epidemiological outcome of a phage outbreak and the prokaryote’s fitness. We show that in the absence of phage evolution, phage extinction is driven by the probability to acquire at least one resistance. However, when phage evolution is fast, phage extinction is driven by an epidemiological critical threshold: any reactivity below this critical threshold leads to phage survival whereas any reactivity above it leads to phage extinction. We also show that in the absence of autoimmunity, high levels of reactivity evolve. However, when CRISPR-Cas systems are prone to autoimmune reactions, intermediate levels of reactivity are evolutionarily optimal. These results help explaining why natural CRISPR-Cas systems do not show high levels of reactivity.

Genomics of Alzheimer’s disease implicates the innate and adaptive immune systems

2021 ◽  
Author(s):  
Yihan Li ◽  
Simon M. Laws ◽  
Luke A. Miles ◽  
James S. Wiley ◽  
Xin Huang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Immune Systems ◽  
Adaptive Immune ◽  
Adaptive Immune Systems

Vitamin D and COVID-19: Insight on Mechanism and Implementation in Equatorial Countries

2021 ◽  
Vol 71 (2) ◽  
pp. 61-64
Author(s):  
Indah Bachti Setyarini ◽  
Nurul Ratna ◽  
Ninik Mudjihartini
Keyword(s):  
Vitamin D ◽  
Immune System ◽  
Severe Acute Respiratory Syndrome ◽  
Ultraviolet Radiation ◽  
Limited Information ◽  
Immunomodulatory Effects ◽  
Immune Systems ◽  
Adaptive Immune ◽  
Global Pandemic ◽  
Adaptive Immune Systems

Coronavirus disease 2019 (COVID-19) is a global pandemic caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection, affecting millions of people worldwide due to its ease of transmission. Despite limited information on effective therapeutic options, vitamin D has been regularly reported to exert beneficial immunomodulatory effects affecting both innate and adaptive immune systems. As it is synthesized in the skin under ultraviolet radiation, population living in equatorial countries are presumed to have adequate vitamin D, however several studies have shown otherwise. This article is aimed to give an insight on the different mechanisms by which vitamin D affects our immune system in COVID-19, as well as discussing correlation of having sunlight all year round by being near the equator towards vitamin D adequacy.

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